Bcl-xL is an Antiapoptotic Regulator for Postnatal CNS Neurons
Bcl-xL is an Antiapoptotic Regulator for Postnatal CNS Neurons
复制标题
DOI：
10.1523/jneurosci.18-03-01009.1998
复制
发表时间：
1998-02
期刊：
影响因子：
--
通讯作者：
A. Parsadanian;Yu Cheng;C. Keller-Peck;D. Holtzman;W. Snider
中科院分区：
文献类型：
--
作者：
A. Parsadanian;Yu Cheng;C. Keller-Peck;D. Holtzman;W. Snider
Bcl-xL是Bcl-2/Ced 9蛋白家族的死亡抑制成员，其促进或抑制细胞凋亡。基因靶向研究表明，Bcl-xL是大脑发育过程中神经元存活所必需的;然而，Bcl-xL基因敲除小鼠不能存活超过胚胎第13.5天，排除了在发育后期对Bcl-xL功能的分析。Bcl-xL表达在出生后的CNS中维持在高水平，这表明它也可以调节出生后时期的神经元存活。为了探索Bcl-xL在出生后神经元存活中的功能，我们在泛神经元启动子的控制下产生了过表达humanBcl-xL的转基因小鼠。选择在脑干中显示强过表达的细胞系和在海马和皮质中显示过表达的细胞系进行分析。我们通过研究两种导致大量神经元凋亡的损伤模式，询问Bcl-xL的过度表达是否影响出生后神经元的存活。在标准的新生儿面部轴突切断术范例中，Bcl-xLover过表达具有实质性影响，轴突切断术后7天运动神经元的存活率为65%，而非转基因同窝仔中仅为15%。为了研究Bcl-xL是否调节前脑中CNS神经元的存活，我们在新生小鼠中使用了缺氧缺血范例。我们在这里表明，缺氧缺血导致大量的野生型新生小鼠的海马和皮层细胞凋亡。此外，我们表明，Bcl-xL的过表达是在这种模式的神经保护。我们的结论是，Bcl-xL在出生后的神经元的水平可能是一个关键的决定因素，他们对凋亡的敏感性。
Bcl-xL is a death-inhibiting member of the Bcl-2/Ced9 family of proteins which either promote or inhibit apoptosis. Gene targeting has revealed that Bcl-xL is required for neuronal survival during brain development; however,Bcl-xL knock-out mice do not survive past embryonic day 13.5, precluding an analysis of Bcl-xLfunction at later stages of development. Bcl-xL expression is maintained at a high level postnatally in the CNS, suggesting that it may also regulate neuron survival in the postnatal period. To explore functions of Bcl-xL related to neuron survival in postnatal life, we generated transgenic mice overexpressing humanBcl-xL under the control of a pan-neuronal promoter. A line that showed strong overexpression in brainstem and a line that showed overexpression in hippocampus and cortex were chosen for analysis. We asked whether overexpression of Bcl-xLinfluences neuronal survival in the postnatal period by studying two injury paradigms that result in massive neuronal apoptosis. In the standard neonatal facial axotomy paradigm, Bcl-xLoverexpression had substantial effects, with survival of 65% of the motor neurons 7 d after axotomy, as opposed to only 15% in nontransgenic littermates. To investigate whether Bcl-xLregulates survival of CNS neurons in the forebrain, we used a hypoxia–ischemia paradigm in neonatal mice. We show here that hypoxia–ischemia leads to substantial apoptosis in the hippocampus and cortex of wild-type neonatal mice. Furthermore, we show that overexpression of Bcl-xL is neuroprotective in this paradigm. We conclude that levels of Bcl-xL in postnatal neurons may be a critical determinant of their susceptibility to apoptosis.